May 30, 2013 (NOT-OD-13-074) -
NIH to Require Use of Updated Electronic Application Forms for Due Dates on or after September 25, 2013. Forms-C applications are required for due dates on or after September 25, 2013.

This Funding Opportunity Announcement (FOA) encourages
applications to study human and non-human stem cells involved in
alcohol-induced tissue injuries. Alcohol abuse is known to cause pathology in
a number of organ systems. Disorders most commonly associated with chronic
alcohol consumption include alcoholic liver disease (ALD), pancreatitis,
cardiovascular disease, neural damage, endocrine dysfunction, osteoporosis,
cancer, and immune dysfunction. The objective of this FOA is to understand
the role of stem cells in alcohol-induced tissue damage and recovery,
particularly how they are influenced by alcohol metabolism and their role in
alcohol-related cancers.

Key Dates

Posted Date

July 10, 2012

Open Date (Earliest Submission Date)

September 16, 2012

Letter of Intent Due Date

Not Applicable.

Application Due Date(s)

Standard
dates apply, by 5:00 PM local time of applicant organization.

It is critical that applicants follow the instructions in
the SF
424 (R&R) Application Guide, except where instructed to do otherwise
(in this FOA or in a Notice from the NIH Guide for Grants and
Contracts). Conformance to all requirements (both in the
Application Guide and the FOA) is required and strictly enforced. Applicants
must read and follow all application instructions in the Application Guide as
well as any program-specific instructions noted in Section IV. When the program-specific
instructions deviate from those in the Application Guide, follow the
program-specific instructions. Applications that do not comply with
these instructions may be delayed or not accepted for review.

There are several options to submit your application to the agency through Grants.gov. You can use the ASSIST system to prepare, submit and track your application online. You can download an application package from Grants.gov, complete the forms offline, submit the completed forms to Grants.gov and track your application in eRA Commons. Or, you can use other institutional system-to-system solutions to prepare and submit your application to Grants.gov and track your application in eRA Commons.
Learn more.

Stem cells have the potential to develop into many different
types of cells, tissues, and organs. Stem cells are characterized by their
capacity of multi-potency of differentiation and self-renewal. They play a
crucial role in many aspects of biology, from embryonic development to tissue
repair and maintenance. While stem cells were first described more than a
century ago, only in the 1970s were hematopoietic stem cells successfully used
in clinic for bone marrow transplantation to treat leukemia. The development of
a method to culture human embryonic stem (ES) cells by Thomson and colleagues
in 1998 overcame a critical technical barrier. Since that time, many research
interests have been focused on ES cells and adult stem cells from several
tissues. Another breakthrough occurred in 2006 when Yamanaka’s laboratory
reprogrammed mouse adult cells into pluripotent stem cells by introducing four
key transcription factors (Oct3/4, Sox2, c-Myc, and Klf4), which had been known
to play an important role in stem cell maintenance. A year later, the work was
reproduced in human skin fibroblasts by Yamanaka’s laboratory using the same
combination of genes, and also independently by Thomson’s laboratory by overexpressing
OCT3/4, SOX2, NANOG, and LIN28. This new category of stem cells is called
induced pluripotent stem (iPS) cells. The success of reprogramming terminally
differentiated human adult cells into iPS cells has offered great opportunities
for stem cell research and personalized regenerative medicine.

Alcohol abuse can cause severe damage to the liver, pancreas
and other tissues, and can even lead to cancer. Stem/progenitor cells in liver,
central nervous system, cardiovascular system, gut, pancreas and maybe in
oral/pharyngeal tissues actively participate in the repair and functional
recovery process from damage caused by alcohol and its metabolites. Recent
advances in stem cell studies provide new tools to further elucidate mechanisms
of alcohol-related pathological conditions, such as alcoholic liver disease,
brain degeneration, pancreatitis, and fetal alcohol syndrome. They may also
provide us with new therapeutic strategies to treat these disorders.

Liver Injury

The liver is a central organ for homeostasis. Its numerous
functions include metabolism, storage, biosynthesis of various biochemical
components, and drug detoxification. Liver injury can be caused by viral
infection, drugs, excessive alcohol consumption, in addition to many genetic,
metabolic and immune disorders. Alcohol toxicity to liver is a function of the
duration of alcohol usage, the amount and frequency of intake of alcohol. Other
factors may also play a significant role in mitigating the response, such as a patient's
nutrition and/or concomitant viral infection. For instance, drinking too much
(more than 5 drinks for men and 4 drinks for women/day) and too often over a
long period of time results in alcoholic liver disease (ALD), characterized by
fatty liver, steatohepatitis, liver fibrosis, and cirrhosis, and may proceed to
hepatocellular carcinoma. Stem cells participate in both tissue pathogenesis
and the recovery process in ALD. In animal experiments of liver
transplantation, hepatocytes can clonally expand, suggesting that hepatocytes
are themselves functional stem cells. Certain types of severe liver injury,
especially when the proliferative capacity of hepatocytes is impaired, can
activate a potential stem cell compartment in the intrahepatic biliary tree.
These cells are the bipotential oval cells (OC), which could differentiate into
hepatocytes and biliary epithelial cells. Bone marrow cells can migrate to the
damaged liver and differentiate into myofibroblasts. Myofibroblasts play a
central role in the pathogenesis of liver fibrosis, and even in the development
of hepatocellular carcinoma. In alcohol-induced chronic hepatitis, a close
correlation has been observed between the degree of progenitor/stem cell
activation and the severity of inflammation and fibrosis. While hepatocytes
carry out important tasks such as drug metabolism and maintenance of glucose
and lipid levels, OC proliferate following certain types of liver injury.

Neural Damage

Excessive alcohol intake is associated with structural and
functional changes in the adult and developing central nervous system (CNS),
manifested by brain atrophy and progressive neurodegeneration, as well as
neurodevelopmental disorders such as fetal alcohol syndrome. Recent research
demonstrates that neural stem cells (NSCs) divide throughout life and give rise
to new neurons. During neurogenesis-proliferation and differentiation of NSC's
into neurons and other types of brain cells are heavily regulated by genetic
and environmental factors, many of which are associated with excessive alcohol
use. Although alcohol causes global changes in the CNS, some brain structures
exhibit heightened sensitivity to alcohol effects and/or toxicity. For
instance, hippocampal dysfunction and neurodegeneration commonly occur as a
result of the neurotoxic effects of alcohol. NSCs in adult brains, essential
for the normal process of neurogenesis, may also have functional significance
in alcohol abusers leading to neural damage and alterations in the homeostasis
of hippocampal structures. It is important to understand the contributions of
neural stem cells to neurogenesis, including repair and regeneration during
abstinence from alcohol and how these are altered in chronic alcohol users.
Studying the roles of neural stem cells on hippocampal function may elucidate
mechanisms underlying hippocampal dysfunctions, such as learning, memory, and
mood disorders in chronic alcoholism.

Cancer

Chronic ethanol consumption may promote carcinogenesis
through its metabolite acetaldehyde, through inflammation, increased oxidative
stress, or induction of cytochrome P4502E1 (CYP2E1), which can convert
pro-carcinogens to carcinogens. Alcohol can interact with other risk factors,
such as viral infection, smoking, obesity and diabetes, in the initiation and
progression of cancers. Furthermore, alcohol may affect the stem cell niche by
perturbing many biochemical or signaling pathways known to be important for
both stem cells and cancers. Examples of these pathways include Notch,
Hedgehog, Wnt/β-catenin, EGF-like/EGFR/Neu, LIF, TGF-β, integrins,
telomerase, SDF-1/CXCR4, prolactin/growth hormone (GH), the IGF-1, Estrogen
Receptor (ER), and Stat3 pathways. Alcohol and its metabolites may interfere
with the renewal or differentiation of stem cells or cancer stem cells by
affecting one or more of these pathways.

Other systems

Stem cells also play an important role in both the
pathological and recovery processes in pancreatitis, cardiovascular disease,
endocrine dysfunction, osteoporosis, and immune dysfunction.

Research
Objectives

Recent advances in the field of stem cells have provided
great opportunities to understand the underlying mechanisms of alcohol-induced
tissue injury and alcohol-related cancers, and to explore new therapeutic
strategies for their diagnosis and treatment. The following examples illustrate
areas of interest:

There is a need to generate disease models that resemble
diverse human polymorphism in alcohol metabolizing enzymes. These genetic
variant models are of great value to more effectively study the effects of
alcohol on stem cell populations and potential pharmacotherapy for
alcohol-induced pathology. Most of the currently used human cell lines carry
genetic and epigenetic artifacts as a result of accommodation to long term
tissue culture. Primary human hepatocytes have a limited life span in vitro.
Most liver cell lines used today are from malignant tissues or have been genetically
modified to gain immortalization. One way might be to explore the phenotypic
outcome by iPS cell technology, or other cell reprogramming technologies, to
produce create a bank of genetically variable iPS cell lines from normal
populations and from well-characterized alcohol-consuming human populations
(although iPSCs may also retain epigenetic marks characteristic of the donor
cell which could influence their differentiation propensity). These models can
be used to study the interaction of alcohol with genetic, epigenetic, and
environmental factors in different genetic models involving Alcohol
Dehydrogenase (ADH), Aldehyde Dehydrogenase (ALDH), CYP2E1, and Glutathione S
transferase (GST) enzymes. In addition, creating a bank of iPS cell lines from
genetically variant patients and normal populations can provide a source for
testing new therapeutic drugs on alcohol induced tissue injury in a more
effective manner.

Improving animal models for alcohol research.

It is important to find better approaches for isolating,
expanding and reprograming specific populations of stem/progenitor cells in
liver and other alcohol related organs. It is also necessary to find animal or
chimeric animal models to study human stem cell (including iPS cells) biology,
in order to better understand the damaging/recovery process in these specific
diseases or disorders

Alcohol's effect on stem cells:

It is important to study alcohol’s effect on endogenous
adult stem/progenitor cells, their self-renewal, proliferation, differentiation,
transformation, and niche. A full description of the role of adult stem cells
in tissue regeneration during alcohol consumption is important for
understanding normal and disease-state physiological and pathological
processes, and for designing therapeutic approaches. Interaction of exogenous
stem cells and endogenous liver stem/progenitor cells in tissue
regeneration/repairing of alcohol induced liver injuries, especially the
mechanism by which transplanted stem cells integrate into hepatic tissue, are
of great importance for clinical use of stem cells.

Characterization of cancer stem cells
in alcohol-related cancers:

Investigation of the mechanisms underlying alcohol’s effect
on liver stem cells and hepatocellular carcinoma (HCC) including genetic and
epigenetic changes is of great importance. Investigation of the roles of
polymorphisms of alcohol-related metabolic genes (e.g., ADH, ALDH, CYP2E1, and
MTHFR) in liver stem cell and alcohol-related liver cancers along with the
interactions of alcohol and its metabolites (especially acetaldehyde) with
other risk factors, such as viral infection, smoking and nutritional disorders,
in alcohol-related liver cancers are also critical for a full understanding of
the constellation of disease presentations seen in chronic alcohol used
disorders.

Investigation of the ability of different types of stem
cells (e.g., liver stem/progenitor cells, bone marrow derived stem/progenitor
cells, embryonic stem cells and iPS cells) to self-renew, proliferate and
differentiate as a function of alcohol use and abuse are encouraged as is the
examination of changes in genes and proteins, and signaling pathways regulating
these changes, and the development of markers and assays that permit accurate
and reliable characterization of alcohol induced specific effect on stem cells.

Section II. Award Information

Funding Instrument

Grant

Application Types Allowed

New
Resubmission
Revisions

The OER
Glossary and the SF 424 (R&R) Application Guide provide details on
these application types.

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH
appropriations, and the submission of a sufficient number of meritorious
applications.

Award Budget

The combined budget for direct costs for the two year
project period may not exceed $275,000. No more than $200,000 may be
requested in any single year. Applicants may request direct costs in $25,000
modules, up to the total direct costs limitation of $275,000 for the combined
two-year award period.

Award Project Period

Scope of the proposed project should determine the project
period. The maximum period is 2 years.

NIH grants policies as
described in the NIH
Grants Policy Statementwill
apply to the applications submitted and awards made in response to this FOA.

Section III. Eligibility
Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

Public/State Controlled Institutions of Higher Education

Private Institutions of Higher Education

The following types of Higher Education Institutions
are always encouraged to apply for NIH support as Public or Private
Institutions of Higher Education:

Applicant organizations must complete the following registrations
as described in the SF 424 (R&R) Application Guide to be eligible to apply
for or receive an award. Applicants must have a valid Dun and Bradstreet
Universal Numbering System (DUNS) number in order to begin each of the following
registrations.

All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s))
must also work with their institutional officials to register with the eRA
Commons or ensure their existing eRA Commons account is affiliated with the eRA
Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant
organizations are strongly encouraged to start the registration process at
least 4-6 weeks prior to the application due date.

Eligible Individuals (Program Director(s)/Principal
Investigator(s))

Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Program Director(s)/Principal
Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH support.

Applicant organizations may submit more than one application,
provided that each application is scientifically distinct.

NIH will not accept any application in response to this FOA
that is essentially the same as one currently pending initial peer review
unless the applicant withdraws the pending application. NIH will not accept any
application that is essentially the same as one already reviewed. Resubmission applications may be submitted, according to the NIH Policy on Resubmission
Applications from the SF 424 (R&R) Application Guide.

Section IV. Application and Submission Information

1. Requesting an
Application Package

Applicants must download the SF424 (R&R) application
package associated with this funding opportunity using the “Apply for Grant
Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in
the SF424
(R&R) Application Guide, except where instructed in this funding
opportunity announcement to do otherwise. Conformance to the requirements in
the Application Guide is required and strictly enforced. Applications that are
out of compliance with these instructions may be delayed or not accepted for
review.

The forms package associated with this FOA includes all
applicable components, mandatory and optional. Please note that some
components marked optional in the application package are required for
submission of applications for this FOA. Follow all instructions in the SF424
(R&R) Application Guide to ensure you complete all appropriate “optional”
components.

Page Limitations

All page limitations described in the SF424 Application
Guide and the Table of
Page Limits must be followed.

PHS 398 Research Plan Component

All instructions in the SF424 (R&R) Application Guide
must be followed, with the following additional instructions:

Resource Sharing Plan

Individuals are required to comply with the
instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model
Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424
(R&R) Application Guide.

Appendix

Do not use the Appendix to circumvent page limits. Follow
all instructions for the Appendix as described in the SF424 (R&R)
Application Guide.

Foreign Institutions

Foreign (non-US) institutions must follow policies described
in the NIH
Grants Policy Statement, and procedures for foreign institutions described
throughout the SF424 (R&R) Application Guide.

3. Submission Dates and
Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in
advance of the deadline to ensure they have time to make any application
corrections that might be necessary for successful submission.

Organizations must submit applications via Grants.gov, the online portal to find and apply for grants
across all Federal agencies. Applicants must then complete the submission
process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants
administration.

Applicants
are responsible for viewing their application in the eRA Commons to ensure accurate
and successful submission.

Information on the submission process and a definition of
on-time submission are provided in the SF424 (R&R) Application Guide.

For assistance with your electronic application or for more information on the electronic submission
process, visit Applying
Electronically.

Important
reminders:All PD(s)/PI(s) must include their eRA Commons ID in the
Credential fieldof the Senior/Key Person Profile Component of the SF
424(R&R) Application Package. Failure to register in the Commons and
to include a valid PD/PI Commons ID in the credential field will prevent the
successful submission of an electronic application to NIH.

The applicant organization must ensure that the DUNS number it provides on the
application is the same number used in the organization’s profile in the eRA
Commons and for the Central Contractor Registration (CCR). Additional
information may be found in the SF424 (R&R) Application Guide.

Upon receipt, applications will be evaluated for completeness
by the Center for Scientific Review, NIH. Applications that are incomplete will
not be reviewed.

Post Submission Materials

Applicants are required to follow the instructions for
post-submission materials, as described in NOT-OD-10-115.

Section V. Application Review Information

1.
Criteria

Only the review criteria described below will be considered
in the review process. As part of the NIH mission,
all applications submitted to the NIH in support of biomedical and behavioral
research are evaluated for scientific and technical merit through the NIH peer
review system.

The R21 exploratory/developmental grant supports
investigation of novel scientific ideas or new model systems, tools, or
technologies that have the potential for significant impact on biomedical or
biobehavioral research. An R21 grant application need not have extensive
background material or preliminary information. Accordingly, reviewers will
focus their evaluation on the conceptual framework, the level of innovation,
and the potential to significantly advance our knowledge or understanding.
Appropriate justification for the proposed work can be provided through
literature citations, data from other sources, or, when available, from
investigator-generated data. Preliminary data are not required for R21
applications; however, they may be included if available.

Overall Impact

Reviewers will provide an overall impact/priority score to
reflect their assessment of the likelihood for the project to exert a
sustained, powerful influence on the research field(s) involved, in
consideration of the following review criteria and additional review criteria
(as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in
the determination of scientific merit, and give a separate score for each. An
application does not need to be strong in all categories to be judged likely to
have major scientific impact. For example, a project that by its nature is not
innovative may be essential to advance a field.

Significance

Does the project address an important problem or a
critical barrier to progress in the field? If the aims of the project are
achieved, how will scientific knowledge, technical capability, and/or clinical
practice be improved? How will successful completion of the aims change the
concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other
researchers well suited to the project? If Early Stage Investigators or New
Investigators, or in the early stages of independent careers, do they have
appropriate experience and training? If established, have they demonstrated an
ongoing record of accomplishments that have advanced their field(s)? If the
project is collaborative or multi-PD(s)/PI(s), do the investigators have
complementary and integrated expertise; are their leadership approach,
governance and organizational structure appropriate for the project?

Innovation

Does the application challenge and seek to shift
current research or clinical practice paradigms by utilizing novel theoretical
concepts, approaches or methodologies, instrumentation, or interventions? Are
the concepts, approaches or methodologies, instrumentation, or interventions
novel to one field of research or novel in a broad sense? Is a refinement,
improvement, or new application of theoretical concepts, approaches or
methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses
well-reasoned and appropriate to accomplish the specific aims of the project?
Are potential problems, alternative strategies, and benchmarks for success
presented? If the project is in the early stages of development, will the
strategy establish feasibility and will particularly risky aspects be managed?

If the project involves clinical research, are the plans for 1) protection of
human subjects from research risks, and 2) inclusion of minorities and members
of both sexes/genders, as well as the inclusion of children, justified in terms
of the scientific goals and research strategy proposed?

Environment

Will the scientific environment in which the work
will be done contribute to the probability of success? Are the institutional
support, equipment and other physical resources available to the investigators
adequate for the project proposed? Will the project benefit from unique
features of the scientific environment, subject populations, or collaborative
arrangements?

Additional Review Criteria

As applicable for the project proposed, reviewers will
evaluate the following additional items while determining scientific and
technical merit, and in providing an overall impact/priority score, but will
not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their
participation according to the following five review criteria: 1) risk to
subjects, 2) adequacy of protection against risks, 3) potential benefits to the
subjects and others, 4) importance of the knowledge to be gained, and 5) data
and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or
more of the six categories of research that are exempt under 45 CFR Part 46,
the committee will evaluate: 1) the justification for the exemption, 2) human
subjects involvement and characteristics, and 3) sources of materials. For
additional information on review of the Human Subjects section, please refer to
the Human
Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and
Children

When the proposed project involves clinical research,
the committee will evaluate the proposed plans for inclusion of minorities and
members of both genders, as well as the inclusion of children. For additional
information on review of the Inclusion section, please refer to the Human
Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live
vertebrate animals as part of the scientific assessment according to the
following five points: 1) proposed use of the animals, and species, strains,
ages, sex, and numbers to be used; 2) justifications for the use of animals and
for the appropriateness of the species and numbers proposed; 3) adequacy of
veterinary care; 4) procedures for limiting discomfort, distress, pain and
injury to that which is unavoidable in the conduct of scientifically sound
research including the use of analgesic, anesthetic, and tranquilizing drugs
and/or comfortable restraining devices; and 5) methods of euthanasia and reason
for selection if not consistent with the AVMA Guidelines on Euthanasia. For
additional information on review of the Vertebrate Animals section, please
refer to the Worksheet
for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures
proposed are potentially hazardous to research personnel and/or the
environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

For Resubmissions, the committee will evaluate the
application as now presented, taking into consideration the responses to
comments from the previous scientific review group and changes made to the
project.

Renewals

Not Applicable.

Revisions

For Revisions, the committee will consider the
appropriateness of the proposed expansion of the scope of the project. If the
Revision application relates to a specific line of investigation presented in
the original application that was not recommended for approval by the committee,
then the committee will consider whether the responses to comments from the
previous scientific review group are adequate and whether substantial changes
are clearly evident.

Additional Review Considerations

As applicable for the project proposed, reviewers will
consider each of the following items, but will not give scores for these items,
and should not consider them in providing an overall impact/priority score.

Applications from Foreign
Organizations

Reviewers will assess whether the project presents
special opportunities for furthering research programs through the use of
unusual talent, resources, populations, or environmental conditions that exist
in other countries and either are not readily available in the United States or
augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in
this section of the application, including 1) the Select Agent(s) to be used in
the proposed research, 2) the registration status of all entities where Select
Agent(s) will be used, 3) the procedures that will be used to monitor
possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety,
biocontainment, and security of the Select Agent(s).

Reviewers will consider whether the budget and the
requested period of support are fully justified and reasonable in relation to
the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical
merit by (an) appropriate Scientific Review Group(s), convened by the NIAAA, in accordance with NIH peer
review policy and procedures, using the stated review
criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

May undergo a selection process in which only those applications
deemed to have the highest scientific and technical merit (generally the top
half of applications under review) will be discussed and assigned an overall impact/priority
score.

Will receive a written critique.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications
will compete for available funds with all other recommended applications . Following initial peer review, recommended applications will receive a second level of
review by the national Advisory Council on Alcohol Abuse and Alcoholism. The following will be considered in making funding decisions:

Scientific and technical merit of the proposed project as
determined by scientific peer review.

Availability of funds.

Relevance of the proposed project to program priorities.

3. Anticipated Announcement
and Award Dates

After the peer review of the application is completed, the
PD(s)/PI(s) will be able to access his or her Summary Statement (written
critique) via the eRA Commons.

If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH
Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided
to the applicant organization for successful applications. The NoA signed by
the grants management officer is the authorizing document and will be sent via
email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection
of an application for award is not an authorization to begin performance. Any
costs incurred before receipt of the NoA are at the recipient's risk. These
costs may be reimbursed only to the extent considered allowable pre-award costs.

A final progress report, invention
statement, and the expenditure data portion of the Federal Financial Report are
required for closeout of an award, as described in the NIH
Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of
2006 (Transparency Act), includes a requirement for awardees of Federal grants
to report information about first-tier subawards and executive compensation
under Federal assistance awards issued in FY2011 or later. All awardees of
applicable NIH grants and cooperative agreements are required to report to
the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH
Grants Policy Statement for additional information on this reporting
requirement.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity
and welcome the opportunity to answer questions from potential applicants.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and
under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.